Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C4, Canada.
Mol Cell. 2024 Apr 4;84(7):1377-1391.e6. doi: 10.1016/j.molcel.2024.02.001. Epub 2024 Feb 28.
Micronuclei (MN) are induced by various genotoxic stressors and amass nuclear- and cytoplasmic-resident proteins, priming the cell for MN-driven signaling cascades. Here, we measured the proteome of micronuclear, cytoplasmic, and nuclear fractions from human cells exposed to a panel of six genotoxins, comprehensively profiling their MN protein landscape. We find that MN assemble a proteome distinct from both surrounding cytoplasm and parental nuclei, depleted of spliceosome and DNA damage repair components while enriched for a subset of the replisome. We show that the depletion of splicing machinery within transcriptionally active MN contributes to intra-MN DNA damage, a known precursor to chromothripsis. The presence of transcription machinery in MN is stress-dependent, causing a contextual induction of MN DNA damage through spliceosome deficiency. This dataset represents a unique resource detailing the global proteome of MN, guiding mechanistic studies of MN generation and MN-associated outcomes of genotoxic stress.
微核（MN）是由各种遗传毒性应激诱导产生的，并聚集核内和细胞质内的蛋白质，为 MN 驱动的信号级联反应做好准备。在这里，我们测量了暴露于一组六种遗传毒物的人细胞中的微核、细胞质和核部分的蛋白质组，全面描绘了它们的 MN 蛋白图谱。我们发现，MN 组装的蛋白质组与周围的细胞质和母核明显不同，剪接体和 DNA 损伤修复成分缺失，而复制酶的一部分则富集。我们表明，转录活性 MN 内剪接机制的耗竭导致 MN 内 DNA 损伤，这是染色体重排的已知前体。MN 中存在转录机制是应激依赖性的，通过剪接体缺陷导致 MN DNA 损伤的上下文诱导。该数据集代表了一个独特的资源，详细描述了 MN 的全蛋白质组，指导 MN 产生和 MN 相关遗传毒性应激结果的机制研究。
